Canagliflozin attenuates kidney injury, gut-derived toxins, and gut microbiota imbalance in high-salt diet-fed Dahl salt-sensitive rats

Abstract

Purpose

To investigate the effects of canagliflozin (20 mg/kg) on Dahl salt-sensitive (DSS) rat gut microbiota and salt-sensitive hypertension-induced kidney injury and further explore its possible mechanism.

Methods

Rats were fed a high-salt diet to induce hypertension and kidney injury, and physical and physiological indicators were measured afterwards. This study employed 16S rRNA sequencing technology and liquid chromatography–tandem mass spectrometry (LC–MS/MS)-based metabolic profiling combined with advanced differential and association analyses to investigate the correlation between the microbiome and the metabolome in male DSS rats.

Results

A high-salt diet disrupted the balance of the intestinal flora and increased toxic metabolites (methyhistidines, creatinine, homocitrulline, and indoxyl sulfate), resulting in severe kidney damage. Canagliflozin contributed to reconstructing the intestinal flora of DSS rats by significantly increasing the abundance of Corynebacterium spp., Bifidobacterium spp., Facklamia spp., Lactobacillus spp., Ruminococcus spp., Blautia spp., Coprococcus spp., and Allobaculum spp. Moreover, the reconstruction of the intestinal microbiota led to significant changes in host amino acid metabolite concentrations. The concentration of uremic toxins, such as methyhistidines, creatinine, and homocitrulline, in the serum of rats was decreased by canagliflozin, which resulted in oxidative stress and renal injury alleviation.

Conclusion

Canagliflozin may change the production of metabolites and reduce the level of uremic toxins in the blood circulation by reconstructing the intestinal flora of DSS rats fed a high-salt diet, ultimately alleviating oxidative stress and renal injury.

Keywords:

• Gut microbiota
• serum metabolites
• hypertension
• kidney injury
• canagliflozin

Disclosure statement

All authors declare that they have no conflict of interest.

Funding statement

The study was supported by The 2019 Hebei Science and Technology Project (No. 19277787D), The 2019 Hebei Innovation Capability Promotion Project (No. 199776249D), the 2020 medical science research project of Hebei Provincial Health Commission (No. 20200724).

Data availability

The data used to support the findings of this study are available from the corresponding author upon request.